Basic esters of 9, 10-dihydro-9, 10-ethanoanthracene-11-carboxylic acid and derivatives thereof



Patented Mar. 30, 1954 BASIC ESTERS 0F 9,10-DIHYDRO-9,10-ETH- ANOANTHRAGENE -11- CARBOXYLIC ACID AND DERIVATIVES THEREOF William W. Jenkins, Morton Grove, Ill., assignor to G. D. Searle & (30., Chicago, Ill., a corporation of Illinois No Drawing. Application September 24, 1952, Serial No. 311,305

11 Claims. l

The present invention is concerned with a new class oi basic esters of polycarbocyclic acids and, in particular, with the basic esters of 9,10- dihydro 9,10 ethanoanthracene-l1-carboxylic acid and its derivatives. The esters and their salts, which constitute this invention can be represented by the following general structural formula wherein Y and Z are members of the class consisting of hydrogen, lower alkyl, and lower aryl radicals, A is a saturated lower bivalent aliphatic hydrocarbon radical containing at least 2 carbon atoms, and NRR' is either a lower dialkylamino radical or a nitrogen-containing heterocyclic radical attached through a nitrogen in the heterocycle to the radical A.

As shown in the foregoing structural formula the ethane-bridge may be unsubstituted or lowerylene.

The radicals and can be straight or branched chained lower alkyl groups. The radical IIRPU' can also be a nitrogen-containing lower heter cycle such as piperazine, lV-alkylpiperazino, thiamorpholinc, quinolino, and isoquinoline, but of particular interest are the heterocyclic radicals of the type wherein B is either an ethylenecxyethylene radical, as in. the case or the morpholino radical, .or an alkylene chain containing 4 to 7 carbon atoms, 4 to 5 of which are in nuclear position, as in the case of pyrrolidino, piperidino, 2,5-dimethyl pyrrolidino and 2,6-lupetidino radicals.

The organic bases described herein form salts, non-toxic in therapeutic dosage, with a variety of inorganic and strong organic acids, including sulfuric, phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, citric, lactic, maleic, malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, oxalic, ascorbic and related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic and aromatic sulfonic acids. Among such esters are methyl chloride, bromide and iodide; ethyl chloride, propyl chloride, butyl bromide, isobutyl chloride, benzyl chloride, phenethyl chloride, naphthylmethyl chloride, dimethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, propylene chlorohydrln, allyl chloride, methallyl bromide and crotyl bromide.

The acids which constitute the starting materials for this invention are prepared by a Diels- Alder addition of a compound of the type wherein X is hydrogen or a lower alkyl group, and Y and Z are defined as hereinabove, to anthracene. Esterification is carried out preferably by refluxing a solution of the acid with an equivalent of the aminoalkyl halide in an inert solvent such as Z-propanol or acetone. The hydrohalide of the basic ester is thus produced and is separated as such or neutralized and extracted as the basic ester, The basic ester can also be prepared by reacting the acid halide with an excess of the amino alcohol, neutralizing the reaction mixture, and extracting the basic ester.

The esters which constitute the present invention are valuable as intermediates in organic synthesis. The bases and simple acid addition salts are of value because of their action on the cardiovascular system and, especially, as diuretics. The quaternary ammonium salts are likewise active as diuretics and show a potent inhibition of the transmission of autonomic nerve impulses through the sympathetic and parasympathetic ganglia. In addition these salts produce a pro nounced blood pressure lowering effect.

My invention is disclosed in further detail by the following examples which are set forth for the purpose of illustrating this invention, but are in no way to be construed as limiting it in spirit or in scope. It will be apparent to those skilled in the art of organic synthesis that many conventional modifications in methods, conditions and materials can be adopted without departing from the scope of the invention. It these examples temperatures are given uncorrected in degrees centigrade (C.), pressures during vacuum distillation in millimetres (mm.) of mercury, and quantities of materials in parts by weight.

EXAIWPLE 1 p-Diethylaminoethyl ester of 9,10-dihydro-9,10-

ethano-anthmcene-ii-carboxylic acid A mixture of 400 parts of anthracene and 300 parts of methyl acrylate is heated in a bomb at 150-175 C. for 6 hours. The contents of the bomb are then taken up in 1800 parts of methanol and heated with a solution of 400 parts of potassium hydroxide and 400 parts of water at reflux temperature for 4 hours. Most of the solvent is distilled ofi in vacuum and the residue is diluted with 10,000 parts of water, stirred with charcoal and filtered. with the aid of a filter agent. The filtrate is acidified and the gummy product is allowed to granulate slowly. The re sulting solid is collected on a filter, washed with ether, ground and dried at 80 C. Recrystallized from benzene the 9,10-dihydro-9,l-ethanoanthracene-ll-carboxylic acid melts at about 189-191" C.

A mixture of 140 parts of 9,l0-dihydro-9,l0- ethanoanthracene-ll-carboxylic acid and '7'? parts of p-chloroethyldiethylamine in 600 parts of anhydrous Z-propanol is heated at reflux temperature for 7.5 hours, after which the solvent is distilled oh and the residue extracted with water. The aqueous extract is washed with. ether, rendered alkaline by the addition of dilute sodium hydroxide and then extracted with ether. The ether extract is dried over anhydrous calcium sulfate, filtered and evaporated.

parts of the residue are dissolved in 325 parts of absolute ether and an equivalent amount of a 25% solution of hydrogen chloride in anhydrous 2-propanol is added. The crystalline hydrochloride of the B-diethylaminoethyl ester of 9,10-dihyd1'o 9,10 ethanoanthracene ll carboxylic acid separates on chilling. Recrystallized from 2-propanol it melts at about 171.5-172 C.

EXAMPLE 2 9,10-dihydro-9,10 ethanoanthracene 11 carbowylic acid ester of fl-hydroryethyldiethylmethylammonium bromide A mixture of parts of B-diethylaminoethyl 9,10-dihydro-9-10 ethanoanthracene 11 carboxylate and 35 parts of methyl bromide in 200 parts of butanone is heated in a sealed pressure reactor for 1 hour at C. After standing for several hours, the precipitate is collected on a filter. Recrystallized from a mixture of 2-propanol and ethyl acetate, the methobromide of the p-diethylaminoethyl ester of 9,10-dihydro-9,10- ethanoanthracene-ll-carboxylic acid melts at about -151 C. It has the structural formula H CH:

C 01115 H/\ H CaHs COOCHr-CHr-N 4 EXAMPLE 3 s-Diethylaminoethyl ester of 9,10 dihydro 12- methyZ-9,10-ethanoanthracene 11 carbomylic acid A mixture of 400 parts of anthracene and 300 parts of crotonic acid is heated at -180 C.

for 6 hours, cooled, digested with 4000 parts of a hot aqueous solution of 10% sodium hydroxide and then filtered while hot. The filtrate is chilled and the precipitate collected on a filter, pressed dry and dissolved in 10,000 parts of tepid water.

After clarification with charcoal, the aqueous solution is acidified with dilute sulfuric acid and chilled. The 9,10 dihydro 12 methyl 9,10-

ethanoanthracene-ll-carboxylic acid is collected on a filter. It melts at about 190-l91 C.

A mixture of 310 parts of 9,10-dihydro-12- methyl-9,10 ethanoanthracene 11 carboxylic acid and 143 parts of fi-chloroethyldiethylamine in 1600 parts of 2-propanol is heated at reflux temperature for 11 hours and then concentrated in vacuum and extracted with water. The aqueous extract is washed with ether, rendered alkaline by the addition of sodium hydroxide and extracted with ether. The ether extract is dried over anhydrous potassium carbonate. filtered and evaporated. The residue is distilled at about 193-l96 C. and 1 mm. pressure.

To a solution of 135 parts of the c-diethylaminoethyl ester of 9,10-dihydro-12-methyl-9,10- ethanoanthracene-ll-carboxylic acid in 3500 parts of absolute ether one equivalent of a 25% solution of hydrogen chloride in absolute 2-propanol is added. An oil separates which granulates upon scratching. Upon recrystallization from ethyl acetate the hydrochloride melts at about l34135 0.

EXAMPLE 4 9,10 dihydro-l2-methyl-9,10-ethanoanthracenell carboxylic acid ester of fl-hydroacyethgildiethylmethylammonium bromide EXAMPLE 5 'y-(N-morpholinmpropyl ester of 9,1 O-dihydro- 1 2 ethyl-9,1 O-ethanoanthmcene-I 1 -CL7Z70CCZJZC acid A mixture of 400 parts of anthracene and 350 parts of 2-pentenoic acid is heated in a bomb at C. for 6 hours, cooled and extracted with a dilute aqueous solution of sodium hydroxide. The extract is washed with ether, rendered acid by addition of dilute hydrochloric acid, filtered and extracted with ether. The ether extract is stirred with charcoal, filtered and evaporated to yield the 9,10-dihydro-12-ethyl-9,10ethanoanthracene-ll-carboxylic acid.

A mixture of 278 parts of this acid and 165 parts of N-('y-chloropropyl)morpholine in 2030 parts of absolute 2-propanol is heated at reflux temperature for 15 hours after which the 2propanel is distilled off in vacuum and the residue extracted with water. The aqueous solution is washed with ether, rendered alkaline by the addition of ammonum hydroxide and extracted with ether. The ether extract is dried, filtered and evaporated. The -(N-morpholino)propy1 ester of 9,10-dihydro-l2ethyl 9,l-ethanoan thracene-ll-carboxylic acid boils at about 215 220 C. and about 1 mm. pressure with decomposition. It has the structural formula o ore-cm H CH-OOO-CHE-CHZ-CHTN o C Hfl-CHQ EIKAMPLE 6 fl-Dieth-ylaminoethyl ester of 9,10-dihydro-11- methyl-9,10-ethanoanthracene 11 ccrboceylic acid A mixture of 800 parts of anthracene and 3 00 parts of methyl methacrylate is heated in a bomb at 175-180 C. for 7 hours, cooled and taken up in 3000 parts of methanol. After addition of a solution of 800 parts of potassium hydroxide and 800 parts of water, the mixture i heated at reflux temperature for l hours. The solvent is then distilled off under vacuum and the residue treated with 12,000 parts of water and the resulting suspension filtered with a filter aid. The filtrate is acidified with dilute sulfuric acid and gummy precipitate permitted to granulate.

The 9,10-dihydro-11-methyl-9,10-ethanoanthra- -icene-ll-carboxylic acid thus obtained is collected on a filter, ground in a mortar, washed with water and dried at 80 C. Recrystallized from benzene its melts at about 2102l1 C.

A mixture of 264 parts of 9,l0-dihydro-ll- J stirring. The promptly forming white precipitate is collected on a filter. Recrystallized from a mixture of ethyl acetate and 2-propanol; the hydrochloride of fi-diethylaminoethyl 9,10-clihydro=1l'-methyl-9,IO-ethanoanthracene 11 carboxylate melts at about 186.5-187" C.

EXAMPLE '7 9,1 0 dmydro -1 1 -methyl- 9,1 O-ethanoanthracene- 1 -carboa;ylic acid ester of e-hydroscyethy ethylmethylammo'nium bromide Within a few minutes after mixing parts of the fl-diethylaminoethyl ester of 9,10-dihydro ll methyl-9,10-ethanoanthracene-ll-carboxylic acid, 69 parts or methyl bromide and 320 parts of butanene, crystallization occurs. The preci tate is collected on a filter and recrystallized rem a mixture of ethyl acetate and 2-propanol.

The methobroiriicle of the [i-diethylaminoethyl 9,10 dihydro-l l -riethyl-9,l0ethanoanthracenell-earboxylate melts at about 17854795 C. Treatment of a solution of 3 moles of the bromide in 2-propanol with one mole of silver citrate and moles of citric acid by stirring at room temperature, removal of the precipitated silver bromide by filtration and concentration of the filtrate yields the dihydrogen citrate. The cation has the structural formula -Dz'isopropylaminopropyl ester of 9,10-dihydro- 11 ethyl 9,10 ethanoanthraoene 11 ca/rboxylic acid In a bomb a mixture of 800 parts of anthracene and 700 parts of oc-EllhYk-LCIYHC acid is heated at fill- C. for 8 hours and then cooled. The contents of the bomb are extracted with a 5% aqueous sodium hydroxide solution. This extract is washed with ether, clarified with charcoal, and acidified with dilute hydrochloric acid. The pro cipitated acid is collected on a filter.

A mixture of 278 parts of 9,10-dihydroii ethyl-9,10 ethanoanthracenedl-carboxylic acid and 1'78 parts of -chloropropyldiisopropylamine in 2000 parts of anhydrous Z-propanol is heated at reflux temperature for 12 hours, concentrated in vacuum and extracted with water. The aqueous extract is washed with ether and rendered alkaline by addition of dilute sodium hydroxide. The akaline solution is extracted with ether and the ether extract is dried over anhydrous calcium sulfate, stirred with decoloriaing charcoal, filtered and evaporated, yielding the diisopropylaminopropyl ester of 9,10-dihydro-l1-ethyl- 9,10-ethanoanthracene-1l-carboxylic acid as a clear oil which boils at about 226-229 C. and

1 mm. pressure with decomposition. It has the structural formula H CH2 /C2Ht E 0 011mm):

7 EXAMPLEQ N-(2,6-Zupetidino)ethyl ester of 9,10-anhydro- 11,12 diethyl 9,10-ethanoanthmcene 11- carbomylic acid A mixture of 100 parts of 2-ethyl-2-pentenoic acid and 100 parts of anthracene is heated in a. bomb for 9 hours at 1'75185 C., cooled and extracted with a large volume of a aqueous sodium hydroxide solution. The extract is washed with ether, clarified with charcoal, acidified with dilute hydrochloric acid and then extracted with ether. This extract is solvent stripped in vacuo, leaving as a residue the 9,10- dihydro 11,12-diethyl 9,10 ethanoanthracenell-carboxylic acid.

A mixture of 264 parts of this acid and 158 parts of N-(fl-chloroethyl) -2,6-lupetidine in 2509 parts of anhydrous 2-propanol is heated at reflux temperature for 20 hours and then concentrated and extracted with Water. The aqueous extract is washed with ether and rendered alkaline by the addition of dilute potassium hydroxide. The base is extracted with ether and the ether extract dried over anhydrous potassium carbonate, stirred with decolorizing charcoal, filtered and evaporated. The resulting N-(2,6- 1upetidino)ethyl ester of 9,10-dihydro-11,12- diethyl 9,10 ethanoanthracene 11 carboxylic acid is obtained as a clear amber oil which has the structural formula EXAMPLE 10 t-Dimethylaminobutyl ester of 9,10-dihydro-12- phenyl 9,10 ethanoanthracene 11 carborcylic acid A mixture of 100 parts of anthracene and 200 parts of cinnamic acid is heated in a bomb for 12 hours at 180 C. After cooling the contents are extracted with a large volume of 5% aqueous sodium hydroxide solution. The extract is washed with ether, clarified with charcoal, acidiiied with dilute hydrochloric acid and extracted With ether.

dihydro l2 phenyl 9,10 ethanoanthracenell-carboxylic acid melts at about 243 C.

A mixture of 340 parts of this acid and 140 parts of a-chlorobutyldimethylamine in 2000 parts of anhydrous 2-propanol is heated at refiux temperature for 1 5 hours, concentrated and extracted with water. The aqueous extract is dried over anhydrous potassium carbonate, filtered and evaporated to yield the t-dimethylaminobutyl ester of 9,10-dihydro-l2-phenyl- 9,10-ethanoanthracene-1l-carboxylic acid as a clear yellowish oil which has the structural formula H C H- C 013 Recrystallized from anisole the 9,10- r 8 EXAMPLE 11 N 13 diethylaminoethyl 9,10 dihydro 9,10 ethanoanthracene-II-carbo:camide 250 parts of 9,IO-dihydro-Q,10-ethanoanthracene-ll-carboxylic acid are converted into the acid chloride by heating with 119 parts of thionyl chloride, '79 parts of pyridine and 1300 parts of benzene at reflux temperature for 1.5 hours. After cooling the mixture is filtered and the filtrate treated with 116 parts of B-aminoethyldiethylamine and heated at reflux temperature for 5 hours. The solvent is stripped and the solid residue is suspended in absolute ether. The N-ediethylaminoethyl 9,10 dihydro 9,10 ethanoanthracene-ll-carboxamide hydrochloride is collected on a filter. Recrystallized from ethyl acetate it melts at about 136l37.5 C.

I claim:

1. The group of new esters consisting of the bases of the structural formula and the non-toxic acid addition and quaternary salts thereof, wherein Y and. Z are members of the class consisting of hydrogen, lower alkyl and phenyl radicals, A is a lower allzylene radical CH2 CH Q/ \3 wherein A is a lower allzylene radical separating the carboxyl radical and the nitrogen atom by at least two carbon atoms.

3. [i-lDlethylaminoethyl ester of 9,10-dihydro- 9,10,-ethanoanthracene-ll-carboxylic acid.

4. The esters of the structural formula (DH-(lower alkyl) CH (19 C 011-0 0 O AN(lower alkyl) wherein A is a lower alkylene radical separating the carboxylradical and the nitrogen atom byat least two carbon atoms.

9 l 5. The esters of the structural formula wherein A is a lower alkylene radical separating the carboxyl radical and the nitrogen atom by at least two carbon atoms. CH 9. S-Diethylaminoethyl ester of 9,10-dihydro- 11-methyl-9,10-ethanoanthracene ll-carboxylic acid. 10. The esters of the structural formula 0HOO0AN(1ower alkyl); CH/ OH(10wer alkyl) wherein A is a lower alkylene radical separating the carboxyl radical and the nitrogen atom by at least two carbon atoms.

6. p-Diethylaminoethyl ester of 9,10-dihydro- 6 (lower alkyl) 12-methyl-9,10-ethanoanthracene l1-carboxylic 5 acid. 0

7. The esters of the structural formula COO--AN(lower alkyl):

wherein A is a lower alkylene radical separating the carboxyl radical and the nitrogen atom by at least two carbon atoms.

11. The esters of the structural formula CH (lower alkyl) CH co OAN(lower alkyl); wherein A is a lower alkylene radical separating the carboxyl radical and the nitrogen atom by at least two carbon atoms.

8. The esters of the structural formula CHCOO A NUWY alkyl) wherein A is a lower alkylene radical separating the carboxyl radical and the nitrogen atom by at least two carbon atoms and Z is a phenyl radical.

on on,

WILLIAM W. JENKINS.

40 CO0A-N(lower alkyl), No references cited. 

1. THE GROUP OF NEW ESTERS CONSISTING OF THE BASES OF THE STRUCTURAL FORMULA 